Diagnostic markers for multiple epilepsy phenotypes

ABSTRACT

A mammalian KIR 4.1 gene and gene products which are predictive of a susceptibility or predisposition to neurological disorders such as multiple epilepsy phenotypes are provided. Methods of predicting an individual&#39;s susceptibility in developing or having a neurological disorder via detection of these diagnostic markers are also provided. In addition, compositions and methods for identifying compositions for use in the treatment of neurological disorders via these genes and gene products are described.

This application claims the benefit of priority of U.S. ProvisionalPatent Application Ser. No. 60/228,538, filed Aug. 28, 2000, which isherein incorporated by reference in its entirety.

This invention was supported in part by funds from the U.S. government(NIH Grant No. RO1 NS33243) and the U.S. government may therefore havecertain rights in the invention.

FIELD OF THE INVENTION

The present invention relates to the identification of a mammalian gene,the human homolog of which is referred to as KIR 4.1, which isassociated with the suscepetibility of an individual for developing orhaving a neurological disease or disorder such as multiple epilepsyphenotypes. The present invention encompasses nucleic acids, recombinantDNA molecules, and cloned genes and variants thereof of thissusceptibility gene, gene products of this susceptibility gene, as wellas cloning vectors containing the susceptibility gene molecules and hostcells genetically engineered to express these molecules. The presentinvention also relates to methods of identifying compounds whichmodulate expression of this susceptibility gene and/or activity ofproteins expressed thereby and to the use of these compositions astherapeutic agents in the treatment of these neurological diseases ordisorders. In addition, the present invention relates to methods fordiagnostic evaluation, genetic testing and prognosis of neurologicaldiseases or disorders associated with this susceptibility gene.Identification of individuals with mutations in the sequences of the KIR4.1 gene of the present invention is useful as a diagnostic aide forvarious neurological disorders and diseases, and in particular multipleepilepsy phenotypes.

BACKGROUND OF THE INVENTION

The term epilepsy refers to a complex series of over 40 diversedisorders that affect 1-2% of the population (Engle, J. Jr. EpilepsyResearch 1996 26:141-150; McNamara J. Neurosci. 1994 14(6):3413-3425;Charlier et al. Nature Genetics 1998 18(1):53-56). The InternationalLeague against Epilepsy periodically revises the classifications andpublishes the nomenclature used to describe reported epilepsy phenotypes(Epilepsy, Intnl League Coalition 1989 30(4):389-399). The most commonseizure phenotypes observed are idiopathic or primary generalizedepilepsy (PGE), in which abnormal electrical activity spreads across theentire cerebral cortex, and focal epilepsy in which abnormal electricalactivity is restricted to one brain region, usually the temporal lobe(TLE). Although recent studies have successfully identified specificgenetic mutations in some rare seizure phenotypes, those geneticinfluences that predispose humans to common epilepsy types such as TLEand PGE are complex and poorly understood. Genetic influences onepilepsy have been the subject of several recent reviews (Ferraro, T. N.and Buono, R. J. “Genetics of Epilepsy: Mouse and Human Studies” InGenetic Influences on Neural and Behavioral Functions. eds. Plaff et al.1999 CRC Press, Boca Raton, Fla.; Szepetowski, P. and Monaco, A. P.Neurogenetics 1998 1:153-163).

Family and twin studies have provided insights regarding the geneticinfluences on both PGE and TLE (Berkovic et al. Annals of Neurology 199843(4):435-45; Berkovic et al. Annals of Neurology 1996 40(2):227-235;Callenbach et al. Epilepsia 1998 39(3):331-6; Jain et al. Seizure 19987(2):139-43; Miller et al. Genetic Epidemiology 1998 15(1):33-49).Concordance rates in monozygotic twins for certain PGE subtypes arereported to range between 65% and 95%, while concordance rates indizygotic twins are reported at 15-30% (Stoffel, M. and Jan, L. Y.Nature Genetics 1998 18:6-8; Miller et al. Genetic Epidemiology 199815(1):33-49; Jain et al. Seizure 1998 7(2):139-43). Genetic influencesin TLE phenotypes were documented more than 30 years ago and, morerecently, in relatively benign idiopathic forms of TLE (Berkovic et al.Annals of Neurology 1996 40(2):227-235; Neubauer et al. Neurology 199851(6):1608-12; Bray, P. F. and Wiser, W. C. Pediatrics 1965 36:207-211;Bray, P. F. and Wiser, W. C. N. Engl. J. Med. 1964 271:926-933). Theseand other studies provide strong evidence for an inherited component tocommon forms of PGE and TLE. Since these disorders are not inherited ina simple Mendelian fashion, it appears that they arise from multiplegene mutations interacting with environmental factors. In addition,epidemiological evidence in humans demonstrates that relatives ofprobands with PGE or TLE are at increased risk for susceptibility toboth generalized and focal epilepsy compared to individuals in thegeneral population (Ottman et al. Archives of Neurology 199855:339-344), suggesting that different forms of epilepsy may share somesusceptibility loci.

Linkage studies have lead to the identification of gene mutations thatcause several rare epilepsy types and have suggested the chromosomallocations of genes related to a few more common epilepsy types. Juvenilemyoclonic epilepsy (JME) has been the most studied of the PGE subtypesand evidence for linkage on chromosomes 6p and 15q have been reported(Greenberg et al. Amer. K. Medical Genetics 1988 31:185-192; Liu et al.Amer. J. Hum. Genet. 1995 57:368-381). In each case linkage data havebeen replicated in some independent patient groups (Weissbecker et al.Am. J. Human Genetics 1991 38:32-36; Elmslie et al. Human MolecularGenetics 1997 6(8):1329-1334), but not others (Whitehouse et al. Am. J.Hum. Genet. 1993 53:652-662; LeHellard et al. Epilepsia 199940(1):117-9; Sander et al., Am. J. Med. Genetics 1999 88(2):182-7),suggesting that several loci are involved in predisposition toward JME,most likely including loci on human 6p and 15q. Linkage on chromosome 8qhas been reported for common subtypes of idiopathic generalized epilepsysuch as childhood absence or juvenile absence, but not replicated in allpatient groups tested (Zara et al. Human Molec. Genetics 19954(7):1201-1207; Durner et al. Am. J. Hum. Genet. 1999 64(5) :1411-9;Fong et al. Am. J. Hum. Genet. 1998 63(4) :1117-29; Sander et al.published the largest linkage study to date on a collection of Europeanpatients and family members with generalized epilepsy including JME,CAE, and Juvenile Absence Epilepsy (JAE) (Hum. Molec. Genet. 20009(10):1465-1472). The results from this study provide evidence for asusceptibility locus on human chromosome 3q. This location was notpreviously reported in any other linkage study. Furthermore, the resultsdid not replicate any evidence for linkage to 6P), 15q or 8q aspreviously reported by others (Greenberg et al. Amer. J. Med. Genet.1988 31:85-92; Liu et al. Amer. J. Hum Genet. 1995 57:368-381;Weissbecker et al. Am. J. Hum. Genet. 1991 38:32-36; Elmslie et al. Hum.Molec. Genet. 1997 6(8):1329-1334). Thus the heterogeneity of the commonepilepsy types continues to confound the search for seizuresusceptibility factors.

Rare epilepsy types following Mendelian inheritance in families havelead to the identification of specific gene mutations that can causeseizure disorder in humans. Progressive myoclonic epilepsy (PME), a PGEsubtype, shows linkage to markers on human chromosomes 6q and 21q(Serratosa et al. Hum. Molec. Genet. 1995 4(9):1657-1663; Sainz et al.Am. J. Hum. Genet. 1997 61(5):12-5-1209; Lehesjoki et al. Proc. NatlAcad. Sci. USA 1991 88(9):3696-9). PME of the Unverricht-Lundborg typewas traced to a mutation in the gene encoding the protease cystatin B on21q. PME of the Lafora type was traced to a mutation in the geneencoding a novel tyrosine phosphatase on 6q (Pennacchio et al. Science1996 271:1731-4; Minassian et al. Nature Genetics 1998 20(2):171-4;Serratosa et al. Hum. Molec. Genet. 1999 8(2):345-52). Other PGEsubtypes such as autosomal dominant nocturnal frontal lobe epilepsy(ADNFLE) and benign familial neonatal convulsions (BFNC) are linked tomarkers on human chromosomes 8q, and 20q (Lewis et al. Am. J. Hum.Genet. 1993 53:670-675; Wallace et al. J. Med. Genet. 199633(4):308-312; Leppert et al. Nature 1989 337:647-648; Phillips et al.Nature Genet. 1995 10(l):117-123). Mutations in two potassium ionchannel genes (KCNQ2 and KCNQ3) have been identified as the BFNC loci onhuman chromosomes 8q and 20q (Biervert et al. Science 1908 279:403-406;Charlier et al. Nature Genetics 1998 18(1):53-56; Singh et al. NatureGenetics 1998 18(l):25-30); Stoffel, M. and Jan, L. Y. Nature Genetics1998 18:6-8). In addition mutations in a nicotinic acetylcholinereceptor alpha -4 subunit (CHRNA4) on 20q have teen linked to ADWFLE(Steinlein et al. Nature Genetics 1995 11(2):201-203: Steinlein et al.Hum. Molec. Genet. 1997 6(6):943-7) and mutations in a sodium ionchannel SCN1B on 19q have recently been linked to generalized epilepsywith febrile seizures (GEFS, Wallace et al. Nature Genetics 199819:366-70). Partial epilepsy types are associated with regions on humanchromosomes 2q, 10q and 15q (Scheffer et al. Annals of Neurology 199844(6):890-9; Ottman et al. Nature Genetics 1995 10:50-60; Poza et al.Annals of Neurology 1999 45(2):182-8; Neubauer et al. Neurology 199851(6):1608-12) and linkage on Xq and 8p has been detected in rare formsof epilepsy accompanied by mental retardation (Gendrot et al. ClinicalGenetics 1994 45(3):145-153; Ryan et al. Nature Genetics 1997 17:92-95:Ranta et al. Genome Res. 1996 6(5):351-360). Finally there areadditional reports of linkage on 19p for a familial form of febrileseizures (Johnson et al. Hum. Molec. Genet. 1998 7(1) :63-67) and 19qfor benign familial infantile convulsions (Guipponi et al. Hum. Molec.Genet. 1997 6(3):473-477).

Although linkage studies have suggested the locations of genes for thecommon epilepsy forms such as JME, CAE, and TLE, these forms exhibit ahigh degree of clinical heterogeneity and the inheritance patterns arenon-Mendelian, suggesting that multiple gene influences are responsiblefor most common seizure phenotypes. Alternative approaches are needed tohelp identify genes of partial effect in these common epilepsy types andto supplement the linkage work already accomplished and in progress.

One such alternative is to analyze epilepsy candidate genes forvariations and then to demonstrate association of disease withinheritance of specific gene variants. This strategy has already beenshown to be useful since a variation in a kainate type glutamatereceptor is reported to be inherited in patients with idiopathicgeneralized epilepsy more often than predicted by classical genetics.(Sander et al. Am. J. Med. Genet. 1997 74:416-421)

Using a mouse model for epilepsy (Ferraro et al. Mammalian Genome 19978:200-208) , a susceptibility gene for seizures induced by variousmechanisms was localized to a small region of murine chromosome 1(Ferraro et al. J. Neuroscience 1999 19(16):6733-6739).

A sequence variation has now been identified in the homologous humangene, KIR 4.1. Further, it has now been determined that this variationoccurs more frequently in epilepsy patients compared to matchedcontrols.

SUMMARY OF THE INVENTION

The object of the present invention is to identify genes associated withneurological disorders, and in particular multiple epilepsy phenotypes,to provide methods of treating and diagnosing neurological disorders,and to provide methods for identifying compounds for use in thesetherapeutic and diagnostic methods.

In particular, an object of the present invention is to provide amammalian gene comprising the human KIR 4.1 gene or a mammalianhomologue thereof which is associated with neurological disorders ordiseases, and in particular multiple epilepsy phenotypes, and molecules,cloned genes and variants thereof.

Another object of the present invention is to provide mammalian geneproducts encoded by the human KIR 4.1 gene or a mammalian homologuethereof, or fragments or variants thereof, and antibodies immunospecificfor their gene products, or fragments or variants thereof.

Nucleic acid and amino acid sequences for the human KIR 4.1 gene aredisclosed herein. Accordingly, another object of the present inventionis to provide vectors, preferably expression vectors, comprising thenucleic acid sequence, and host cells genetically engineered to expressmammalian susceptibility gene products.

Another object of the present invention is to provide methods of use ofthe human KIR 4.1 gene or mammalian homologues thereof, as well as geneproducts thereof, for the diagnostic evaluation, genetic testing andprognosis of a neurological disorder or disease, in particular anepilepsy phenotype. For example, in one embodiment, a method is providedfor predicting the susceptibility or predisposition of an individual tohaving or developing a neurological disorder or disease such as anepilepsy phenotype by detecting for the presence or absence of the humanKIR 4.1 gene or gene product or mutations thereof. In this method, theabsence of the human KIR 4.1 gene or gene product or the presence of amutation thereof is predictive of susceptibility or predisposition of anindividual to having or developing a neurological disorder such asepilepsy. In another embodiment, a method is provided for diagnosingneurological disorders or diseases such as multiple epilepsy phenotypesin an individual by analyzing for the presence or absence of the humanKIR 4.1 gene or gene product or a variant thereof in a biological sampleobtained from the individual. In this method, the absence of the KIR 4.1gene or gene product or the presence of a variant thereof is indicativeof the individual having a neurological disease or disorder such as anepilepsy phenotype.

Another object of the present invention is to provide new treatments andmethods of identifying new treatments for neurological disorders anddisease such as multiple epilepsy phenotypes. In one embodiment, thesetreatments involve modulation of the expression of the human KIR 4.1gene or a mammalian homologue thereof and/or the activity or synthesisof a gene product of the human KIR 4.1 gene or mammalian homologuesthereof. In another embodiment, treatments involve supplying the mammalwith a nucleic acid molecule encoding normal human KIR 4.1 or amammalian homologue thereof. Methods for identifying new treatmentsinvolving modulation of the expression of the human KIR 4.1 gene ormammalian homologues thereof and/or the synthesis or activity of geneproducts of the human KIR 4.1 gene or mammalian homologues thereofcomprise contacting a compound to a cell that expresses a human KIR 4.1gene or a mammalian homologue thereof, measuring either the level ofexpression of a human KIR 4.1 gene or a mammalian homologue thereof orgene product activity produced by the cell and comparing this level tothe level of expression or in the cell in the absence of the compound.Compounds which alter the level of expression and/or activity of humanKIR 4.1 or mammalian homologues thereof are thus identified asmodulators of this susceptibility gene.

DETAILED DESCRIPTION OF THE INVENTION

A sequence variation in human gene KIR 4.1 has now been identified asoccurring more frequently in epilepsy patients compared to matchedcontrols.

To identify polymorphisms in candidate genes in humans, DNA frompatients with JME, CAE and mesial refractory TLE was analyzed. Acombination of polymerase chain reaction (PCR), single strandconformational polymorphism (SSCP) and DNA sequencing was used formutation detection from genomic DNA. Although only cDNA information isavailable for many candidate genes of interest, insertions, deletionsand single nucleotide polymorphisms that may affect the coding portionsof these genes can still be identified. For mutation detection, reversetranscription was utilized to generate cDNA pools that were used as atemplate and PCR was performed to generate amplified products foranalyses by conformation sensitive gels and DNA sequencing.

Polymorphisms were first screened for in 30 unrelated TLE, 30 unrelatedCAE and 30 unrelated JME patients. The number of patients who carry thevariant out of the total screened yields a measure of “attributablerisk”. Not all persons who are ill from a complex disease would beexpected to have increased risk for illness arising from a singlegenetic variation, thus attributable risk is a measure of mutationfrequency in a given population.

Candidate selection based on mouse linkage data identified KIR 4.1 (alsoknown as KCNJ10) as a high priority candidate gene for further testing.KIR 4.1 has a variation in its DNA coding region that alters an aminoacid. In addition, a threonine residue at position 262 (found in theseizure resistant B6 strain of mice) is conserved in every other speciesfrom which KIR 4.1 has been sequenced including human, rat, and rabbit.

Thus, the human KIR 4.1 gene was searched for sequence variations. Likethe mouse, the human gene contains no introns, a fact that greatlyfacilitated polymorphism detection. It was found that the human KIR 4.1gene, like the mouse gene, has a missense mutation. The mutation inhuman KIR 4.1 is a single nucleotide polymorphism (T1037C of SEQ IDNO:1, C271R of SEQ ID NO:2) that alters the amino acid from a cysteineto an arginine in the putative dimerization domain of the ion channelsubunit. Interestingly, this variation in the human gene (C271R) occursin the same part of the protein as the mouse variation (a SNP causingT262S), just 9 amino acid residues apart from each other.

This single nucleotide polymorphism was analyzed by PCR and SSCP in 138patients of German descent with idiopathic generalized epilepsy (IGE),juvenile absence epilepsy (JAE) and (CAE), 40 temporal lobe epilepsy(TLE) patients of European descent and 128 ethically matched controls.When all ill individuals were combined, chi square analysis of thedistribution of genotpyes showed a significant difference betweenpatients and controls (χ²:p<0.036). These data indicate that thispolymorphism represents a protective allele against seizuresusceptibility in multiple epilepsy phenotypes.

Accordingly, the human KIR 4.1 sequence and variants thereof serve asdiagnostic markers for susceptibility to neurological disorders ordiseases such as multiple epilepsy phenotypes.

The isolated nucleotide sequence of this susceptibility gene is depictedin SEQ ID NO:1. This mammalian gene is referred to herein KIR 4.1. Thisgene has also been referred to as KCNJ10. The deduced amino acidsequence of a gene product encoded by this nucleic acid sequence isdepicted in SEQ ID NO:2. The absence of this mammalian gene or anencoded gene product or the presence of a variant gene or gene productthereof are believed to be indicative of the susceptibility of anindividual to developing and/or having a neurological disorder ordisease such as an epilepsy phenotype. An exemplary variant of the KIR4.1 gene is the single nucleotide polymorphism T1037C of SEQ ID NO:1,C271R of SEQ ID NO:2 that alters the amino acid from a cysteine to anarginine in the putative dimerization domain of the ion channel subunit.Accordingly, the present invention relates to the KIR 4.1 gene and KIR4.1 gene products and their use as diagnostic markers for ascertainingsusceptibility or predisposition of an individual to developing and/orhaving a neurological disorder or disease such as an epilepsy phenotype.The KIR 4.1 gene and gene products and variants thereof are also usefulin identifying new treatments and treating neurological disorders anddiseases such as multiple epilepsy phenotypes.

As used herein by “KIR 4.1 gene” it is meant a nucleic acid moleculecomprising the DNA sequence of SEQ ID NO:1; any DNA sequence thatencodes a polypeptide containing the amino acid sequence comprising SEQID NO:2; and any DNA sequence that hybridizes to the complement of DNAsequences that encode an amino acid sequence comprising SEQ ID NO:2under moderately stringent conditions. By “moderately stringentconditions” it is meant conditions such as those described by Ausubel etal. (1989 Current Protocols in Molecular Biology, Vol. I, GreenPublishing Associates, Inc. and John Wiley & Sons, Inc. N.Y.). As usedherein, “KIR 4.1 gene” also refers to degenerate variants encoding KIR4.1 gene products. An exemplary variant of the KIR 4.1 gene is the SNPof T1037C of SEQ ID NO:1, C271R of SEQ ID NO:2 that alters the aminoacid from a cysteine to an arginine in the putative dimerization domainof the ion channel subunit. KIR 4.1 genes can include both genomic DNAor cDNA and mRNA transcribed by the genomic DNA.

The present invention also relates to KIR 4.1 gene products. By “KIR 4.1gene products” it is meant to include amino acid sequences encoded bythe normal and variant KIR 4.1 genes. This term is also meant to includefunctionally equivalent KIR 4.1 gene products. By “functionallyequivalent” it is meant a gene product with at least one biologicalactivity which is the same as the normal KIR 4.1 gene product.Accordingly, contacting cells with a functionally equivalent KIR 4.1gene product can inhibit or delay the onset of one or more symptoms of aneurological disorder or disease.

Also provided in the present invention are nucleic acid sequences,either DNA, RNA or a combination thereof which hybridize to the KIR 4.1gene. Such hybridization may occur under moderately stringentconditions, or more preferably highly stringent conditions. Suchconditions are well known in the art and discussed in detail inreferences such as Ausubel et al. (1989 Current Protocols in MolecularBiology, Vol. I, Green Publishing Associates, Inc. and John Wiley &Sons, Inc. N.Y.). These nucleic acid sequences can be used as probes inthe detection of normal and variant KIR 4.1 genes. These nucleic acidsequences can also be used as antisense agents altering expression ofnormal or variant KIR 4.1 genes.

The present invention also relates to vectors comprising KIR 4.1 genesand nucleic acid sequences which hybridine to the KIR 4.1 gene. In apreferred embobiment, the vectors are expression vectors with aregulatory element which directs expression of the KIR 4.1 gene or thenucleic acid sequence. The present invention also relates to host cellsgenetically engineered to express KIR 4.1 gene products.

KIR 4.1 genes, KIR 4.1 gene products and variants thereof as well asnucleic acid sequences hybridizing to the KIR 4.1 gene are useful indiagnosing neurological disorders or diseases, identifying newtreatments for neurological disorders or disease and in treatingneurological disorders or disease. In a preferred embodiment, theneurological disorder or disease comprises one of the multiple epilepsyphenotypes.

In one embodiment, individuals with a predisposition to developing orhaving a neurological disorder such as an epilepsy phenotype areidentified by detecting variations in the KIR 4.1 gene of SEQ ID NO:1 oran absence of the KIR 4.1 gene of SEQ ID NO:1. Methods for identifyingindividuals with a known nucleotide sequence or variants thereof arewell known in the art. Examples of such methods include, but are notlimited, polymerase chain reaction (PCR), ligase chain reaction (LCR)and nucleic acid sequence based amplification (NASABA).Reverse-transcriptase PCR (RT-PCR) is also a powerful technique whichcan be used to detect the presence of specific MRNA populations in acomplex mixture of thousands of other mRNA species. In RT-PCR, an mRNAspecies is first reverse transcribed to complementary DNA (cDNA) withuse of the enzyme reverse transcriptase; the cDNA is then amplified asin a standard PCR reaction. RT-PCR can thus reveal by amplification thepresence of a single species of mRNA. Hybridization to clones oroligonucleotides arrayed on a solid support (i.e. gridding) can also beused to detect the presence of a selected nucleotide sequence.

In this method a DNA-containing biological sample is obtained from anindividual. DNA or mRNA in the biological sample is then analyzed forthe presence or absence of the KIR 4.1 gene of SEQ ID NO:1 or a variantthereof. The absence of the KIR 4.1 gene of SEQ ID NO:1 and/or thepresence of a variant gene is indicative of the individual beingsusceptible to developing or having a neurological disorder or diseasesuch as an epilepsy phenotype. An exemplary variant KIR 4.1 is the SNPT1037C of SEQ ID NO:1.

Alternatively, biological samples obtained from an individual can alsobe analyzed for the presence of a variant KIR 4.1 gene product, such asthose depicted in the presence or absence of the KIR 4.1 gene product ofSEQ ID NO:2 to ascertain an individual's susceptibility to theneurological disorder. An exemplary variant gene product is the proteinencoded by the SNP T1037C of SEQ ID NO:1, C271R of SEQ ID NO:2 thatalters the amino acid from a cysteine to an arginine. Methods fordetecting the presence or absence of a known polypeptide sequence arewell known in the art. The KIR 4.1 gene product or variants andfragments thereof can be used to raise antibodies against the KIR 4.1gene product or variant thereof. Such antibodies can then be used invarious assays to detect the presence or absence of the KIR 4.1 geneproduct or variant thereof in a sample. Examples of these assaysinclude, but are not limited to, radioimmunoassays, immunohistochemistryassays, competitive-binding assays, Western Blot analyses, ELISA assays,proteomic approaches, two-dimensional gel electrophoresis (2Delectrophoresis) and non-gel based approaches such as mass spectrometryor protein interaction profiling. In these methods, the presence of avariant KIR 4.1 gene product or the absence of the KIR 4.1 gene productof SEQ ID NO:2 is indicative of an individual being susceptible todeveloping or having a neurological disorder or disease such as anepilepsy phenotype.

The KIR 4.1 gene and KIR 4.1 gene products of SEQ ID NO:1 and SEQ IDNO:2 also provide useful tools for development of new treatments forneurological disorders such as multiple epilepsy phenotype. For example,as demonstrated herein mutations in the nucleotide sequence of SEQ IDNO:1 leads to variants with disrupted protein function in individualswith an epilepsy phenotype. Accordingly, the KIR 4.1 gene product,agents which mimic the KIR 4.1 gene product or inhibit disruption in thefunction of the KIR 4.1 gene product may be useful in treatingneurological disorders or disease such as multiple epilepsy phenotypes.Alternatively, agents which alter expression and/or levels of the normalprotein may also be useful in the treatment of such disorders. Suchagents can be identified in routine screening assays which examinelevels of the KIR 4.1 gene or KIR 4.1 gene product as depicted in SEQ IDNO:1 and SEQ ID NO:2. Agents identified as altering levels and/orexpression of the gene or gene product of SEQ ID NO:1 and SEQ ID NO:2are expected to be useful in the treatment of neurological disorderssuch as multiple epilepsy phenotypes.

The KIR 4.1 gene and KIR 4.1 gene products of SEQ ID NO:1 and SEQ IDNO:2 are also useful in identifying other proteins and/or genes encodingsuch proteins which interact with KIR 4.1 gene products. Various methodsfor identifying such proteins and/or genes for encoding these proteinsare known in the art. Well known techniques include, but are not limitedto, yeast two hybrid systems and receptor binding assays.

1. A diagnostic marker for predicting susceptibility of an individual tohaving or developing idiopathic generalized epilepsy, juvenile absenceepilepsy, childhood absence epilepsy, or temporal lobe epilepsycomprising an isolated human KIR 4.1 nucleic acid molecule of SEQ IDNO:1 or a human KIR 4.1 polypeptide of SEQ ID NO:2, wherein the thymineat position 1037 of the human KIR 4.1 nucleic acid molecule of SEQ IDNO:1 is replaced with cytosine, or the cysteine at position 271 of thehuman KIR 4.1 polypeptide of SEQ ID NO:2 is replaced with an arginine.